1. Field of the Invention
This invention relates to stable 6,9.alpha.-thiaprostacyclin derivatives which are active as inhibitors of blood platelet aggregation and/or which show arterial constriction activities.
2. Description of the Prior Art
The prostaglandins were first discovered in the 1920's and have proven since then to be among the most ubiquitous pharmaceutically active compounds ever tested. Their use and the use of analogs and derivatives thereof, has been suggested in as wide a range of applications as fertility control, induction of labor, regulation of blood pressure, regulation of blood clotting, control of asthma, anticonvulsion, antidepressants, and many others. A new compound has recently been discovered (Nature 263, 663 (1976); Prostaglandins, vol. 12, 685 and 715 (1976); Chem. and Engineering News, Dec. 20, 1976) which belongs to the general family of prostaglandins. The compound has been named prostacyclin and its structure has been proven by synthesis (Johnson, et al, Prostaglandins, 12, 915 (1976); Corey, et al, J. Amer. Chem. Soc., 99, 2006 (1977)) to be that of formula I. (The numbering system for prostacyclins is given for reference): ##STR2## Its generic name is 6,9.alpha.-oxido-11.alpha.,15.alpha.-dihydroxyprosta(Z)5,E(13)dienoic acid. Prostacyclin is the most potent inhibitor of blood platelet aggregation of all the prostaglandins discovered to date. It has also been shown that prostacyclin destroys platelet aggregates after they have formed and that it has, in addition, a powerful action as a dilator of blood vessels. Prostacyclin thus appears to act in exactly opposite ways to thromboxane A.sub.2 another recently discovered member of the prostaglandin family. Thromboxane A.sub.2 causes platelet aggregation and simultaneously act as powerful constrictor of arteries. Both prostacyclin and thromboxane A.sub.2 are derived biosynthetically from a common intermediate, called endoperoxide and they are decomposed by water to prostaglandins. The balance between the levels of prostacyclin and thromboxane A.sub.2, appears to maintain a finely tuned equilibrium between blood platelet aggregation versus dissolution and arterial constriction versus dilation. ##STR3##
The use of prostacyclins has been suggested in the treatment of blood clotting in diseased vessels of patients with cardiovascular problems. Since prostacyclin has retroactive action and not only inhibits blood clotting but also dissolves already formed clots, it can be used in heart attack cases and artherosclerosis. Increased susceptibility of platelets to aggregation accompanies vascular complications in diabetes, in cerebral strokes associated with essential hypertension and in post heart attack cases. These are other areas where prostacyclin activity can be highly beneficial. The main drawback of the use of prostacyclin for these applications is its very short biological half-life of 2 minutes. This prevents the externally provided drug from reaching its target tissues intact. The need to maintain the drug in a totally anhydrous condition also prevents its ready shipment, storage and testing for pharmacological applications. If an analog or derivative of prostacyclin can be formed which is stable and shows similar effects on blood platelets and arteries, it would have wide applications in pharmacology and the treatment of cardiovascular and related diseases. Another application for a stable analog of prostacyclin would be its use as an inhibitor of blood platelet aggregation in externally circulated blood by kidney dialysis machines or heart-lung machines.